Imidazo[1,2-a]pyridines, pharmaceutical compositions containing these compounds and processes for preparing them

Abstract

Imidazo[1,2-a]pyridines of the formula <IMAGE> (I) wherein Ra to Re are as defined herein, the enantiomers and the salts thereof, which are useful as angiotensin antagonists and for treating conditions treatable with angiotensin antagonists.

What is claimed is: 
     
       1. An imidazo[1,2-a]pyridine of the formula ##STR18## wherein R a  denotes a straight-chained or branched C 1-6  -alkyl group, a cycloalkyl group, an alkyl group substituted by an alkoxy group, or a C 1-4  -alkoxy group, R b  denotes a hydrogen, fluorine, chlorine or bromine atom, or an alkyl, hydroxymethyl, trifluoromethyl, formyl, carboxy, alkoxycarbonyl, cyano, nitro, NH 2  CH 2  --, R 1  NHCH 2  -- or R 1  NR 2  CH 2  -- group, wherein R 1  and R 2 , which may be identical or different, denote C 1-6  -alkyl groups, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl groups or   R 1  and R 2  together denote a C 4-6  -n-alkylene group,     R c  denotes a hydrogen, fluorine, chlorine or bromine atom, an alkyl group optionally substituted by an alkoxy or phenylalkoxy group, an alkoxy, phenylalkoxy, trifluoromethyl, H 2  N--, R 1  NH-- or R 1  NR 2  -- group, wherein R 1  and R 2  are as hereinbefore defined,   R d  denotes a hydrogen atom or an alkyl group,   R e  denotes a carboxy group, a group which may be converted in vivo into a carboxy group, or a cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl, alkanesulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, phenylalkanesulphonylaminocarbonyl, trifluoromethanesulphonylaminocarbonyl, phosphino, O-alkyl-phosphino, O-aralkyl-phosphino, phosphono, O-alkyl-phosphono, O-aralkyl-phosphono, O,O-dialkylphosphono, phosphono-methyl, O-alkyl-phosphonomethyl, O-aralkyl-phosphono-methyl, O-aryl-phosphono-methyl, O,O-dialkyl-phosphono-methyl, phosphato, O-alkyl-phosphato, O-aralkyl-phosphato, O-aryl-phosphato or O,O-dialkyl-phosphoryl group,   X denotes an oxygen atom, an imino group optionally substituted by a formyl, R 1  -- or R 1  CO-- group, or a --CO--, --(HON═C)-- or --(R 3  CR 4 )-- group, wherein R 3  is a hydrogen atom or an alkyl group and   R 4  is a hydrogen atom, an alkoxy group substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or heteroaryl group, wherein the heteroaryl group is linked to the alkoxy group via a carbon-carbon bond,   an alkoxy group substituted in the 2, 3 or 4-position by a heteroaryl group, wherein the heteroaryl group is linked to the alkoxy group via a carbon-nitrogen bond,   a hydroxy, dialkylphosphonomethoxy, azido, CHO--O--, R 1  O--, R 5  NR 6  --, R 1  CO--O--, R 1  O--CO--O--, CHO--NR 5  --, R 1  --CO--NR 7  --, R 1  O--CO--NR 5  --, R 5  NR 6  --CO--O--, R 1  SO 2  --O--, R 5  NR 6  -- CO--NR 5  -- or R 1  SO 2  --NR 7  -- group or   R 3  and R 4  together denote a 1,2-ethylenedioxy- or 1,3-n-propylenedioxy group,   wherein in the above-mentioned groups, R 1  is as hereinbefore defined,   R 5  and R 6 , which may be identical or different, represent hydrogen atoms or have the meanings given for R 1  and R 2  hereinbefore,   R 7  denotes a hydrogen atom or an alkyl group or R 1  and R 7  together denote a C 3-5  -n-alkylene group,     wherein, unless otherwise specified, an alkyl or alkoxy moiety mentioned above may contain 1 to 4 carbon atoms and a cycloalkyl moiety mentioned above may contain 3 to 7 carbon atoms, and   the term "an aryl group" denotes a phenyl group optionally mono or disubstituted by a fluorine, chlorine or bromine atom, or by a hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylaminosulphonyl group, wherein each alkyl moiety may contain 1 to 4 carbon atoms, or a naphthyl group and   the term "heteroaryl group" denotes a 5-membered heteroaromatic ring, bound via a carbon atom or an imino group, and containing an imino group, an oxygen or sulphur atom or an imino group and an oxygen, sulphur or nitrogen atom, or denotes a 6-membered heteroaromatic ring bound via a carbon atom and containing 1 or 2 nitrogen atoms, whilst the above-mentioned heteroaromatic rings may be substituted in the carbon skeleton by a C 1-6  -alkyl group or by a phenylalkyl group and there may be attached to both the 5-membered and to the 6-membered heteroaromatic rings, in each case via two adjacent carbon atoms, an n-propylene, n-butylene or 1,3-butadienyl group or, via an imino group and an adjacent carbon atom, an n-butylene or 1,3-butadienyl group, and in an anellated pyridine ring thus formed a methine group may be replaced by a nitrogen atom and a vinylene group in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or in an anellated phenyl ring thus formed one or two methine groups may be replaced by N-atoms, whilst additionally the above-mentioned fused-on aromatic or heteroaromatic rings in the carbon skeleton may be monosubstituted by a fluorine, chlorine or bromine atom, or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylaminosulphonyl group or disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and two methyl substituents in the 1,2-position relative to one another may be linked to one another by a methylene or ethylene bridge and an NH group optionally present in an imidazole ring may be substituted by a C 1-6  -alkyl group, by a phenylalkyl group or by a cycloalkyl group,   or an enantiomer or salt thereof.   
     
     
       2. An imidazo[1,2-a]pyridine as recited in claim 1, wherein R a  denotes a straight-chained or branched C 1-4  -alkyl group, a cyclopropyl, cyclobutyl, alkoxy, methoxymethyl or ethoxymethyl group,   R b  denotes a hydrogen, chlorine or bromine atom, an alkyl, aminomethyl, R 1  NHCH 2  or R 1  NR 2  CH 2  group, wherein R 1  and R 2 , which may be identical or different, denote C 1-4  -alkyl groups, cyclohexyl, phenyl or benzyl groups or   R 1  and R 2  together denote an n-butylene group,     R c  denotes a hydrogen, chlorine or bromine atom, an alkyl or trifluoromethyl group,   R d  denotes a hydrogen atom or an alkyl group,   R e  denotes a carboxy or a 1H-tetrazol-5-yl group,   X denotes an oxygen atom, an imino group optionally substituted by a formyl, R 1  or R 1  CO group, or a CO, --(HON═C)-- or (R 3  CR 4 ) group, wherein R 3  denotes a hydrogen atom or an alkyl group and   R 4  denotes a hydrogen atom, an alkoxy group substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or heteroaryl group, wherein the heteroaryl group is linked to the alkoxy group via a carbon-carbon bond,   an alkoxy group substituted in the 2, 3 or 4-position by a heteroaryl group, wherein the heteroaryl group is linked to the alkoxy group via a carbon-nitrogen bond,   a hydroxy, R 1  O--, R 1  CO--O--, R 1  O--CO--O--, azido, R 5  NR 6  --, CHO--NR 5  --, R 1  --CO--NR 7  --, R 1  O--CO--NR 5  --, R 5  NR 6  --CO--O--, R 1  SO 2  --O--, R 5  NR 6  --CO--NR 5  -- or R 1  SO 2  --NR 7  -- group, wherein in the abovementioned groups, R 1  is as hereinbefore defined,   R 5  and R 6 , which may be identical or different, denote hydrogen atoms or have the meanings given for R 1  hereinbefore,   R 7  denotes a hydrogen atom or an alkyl group or   R 1  and R 7  together denote a C 3-5  -n-alkylene group, whilst unless otherwise specified an alkyl or alkoxy moiety mentioned above may contain 1 to 3 carbon atoms and a cycloalkyl moiety mentioned above may contain 3 to 7 carbon atoms,     or an enantiomer or salt thereof.   
     
     
       3. An imidazo[1,2-a]pyridine as recited in claim 1, wherein R a  denotes a C 2-4  -alkyl group,   R b  denotes a hydrogen atom,   R c  denotes a hydrogen atom or a methyl group,   R d  denotes a hydrogen atom,   R e  denotes a carboxy or 1H-tetrazolyl group and   X denotes a carbonyl group or a methylene group optionally substituted by a hydroxy, methoxy, benzyloxy, pyridylmethoxy, acetoxy, ethoxycarbonylmethoxy, cyclohexyl carbonyloxy or cyclohexylaminocarbonyloxy group,   or an enantiomer or a salt thereof.   
     
     
       4. An imidazo[1,2-a]pyridine as recited in claim 1, selected from the group consisting of: (a) (R,S)-2-ethyl-8-methyl-5-[α-(2'-carboxybiphenyl-4-yl)-α-hydroxy-methyl]imidazo[1,2-a]pyridine,   (b) (R,S)-2-ethyl-8-methyl-5-[α-(2'-carboxybiphenyl-4-yl)-α-acetoxy-methyl]imidazo[1,2-a]pyridine,   (c) (R,S)-2-ethyl-8-methyl-5-[α-(2'-carboxybiphenyl-4-yl)-α-cyclohexylaminocarbonyloxy-methyl]imidazo[1,2-a]pyridine,   (d) (R,S)-2-n-propyl-8-methyl-5-[α-(2'-carboxybiphenyl-4-yl)-α-hydroxy-methyl]imidazo[1,2-a]pyridine,   an enantiomer, and a salt thereof.   
     
     
       5. A pharmaceutical composition useful for treating a condition treatable by an angiotensin antagonist comprising a therapeutically effective amount of an imidazo[1,2-a]pyridine as recited in claim 1 and one or more inert carriers or diluents. 
     
     
       6. A pharmaceutical composition useful for treating a condition treatable by an angiotensin antagonist comprising a therapeutically effective amount of an imidazo[1,2-a]pyridine as recited in claim 2 and one or more inert carriers or diluents. 
     
     
       7. A pharmaceutical composition useful for treating a condition treatable by an angiotensin antagonist comprising a therapeutically effective amount of an imidazo[1,2-a]pyridine as recited in claim 3 and one or more inert carriers or diluents. 
     
     
       8. A pharmaceutical composition useful for treating a condition treatable by an angiotensin antagonist comprising a therapeutically effective amount of an imidazo[1,2-a]pyridine as recited in claim 4 and one or more inert carriers or diluents. 
     
     
       9. A method for treating a patient suffering from a condition treatable by an angiotensin anatgonist, which comprises administering to the patient a therapeutically effective amount of an imidazo[1,2-a]pyridine as recited in claim 1. 
     
     
       10. A method for treating a patient suffering from a condition treatable by an angiotensin anatgonist, which comprises administering to the patient a therapeutically effective amount of an imidazo[1,2-a]pyridine as recited in claim 2. 
     
     
       11. A method for treating a patient suffering from a condition treatable by an angiotensin anatgonist, which comprises administering to the patient a therapeutically effective amount of an imidazo[1,2-a]pyridine as recited in claim 3. 
     
     
       12. A method for treating a patient suffering from a condition treatable by an angiotensin anatgonist, which comprises administering to the patient a therapeutically effective amount of an imidazo[1,2-a]pyridine as recited in claim 4.